Recent advances in understanding the complexities of metastasis

Abstract

Tumour metastasis is a dynamic and systemic process. It is no longer seen as a tumour cell-autonomous program but as a multifaceted and complex series of events, which is influenced by the intrinsic cellular mutational burden of cancer cells and the numerous bidirectional interactions between malignant and non-malignant cells and fine-tuned by the various extrinsic cues of the extracellular matrix. In cancer biology, metastasis as a process is one of the most technically challenging aspects of cancer biology to study. As a result, new platforms and technologies are continually being developed to better understand this process. In this review, we discuss some of the recent advances in metastasis and how the information gleaned is re-shaping our understanding of metastatic dissemination.

Keywords: Biosensors; Cancer; Cancer Therapy; Circulating Tumour Cells; Colonisation; Disseminated Tumour Cells; Dormancy; Extracellular Matrix; Extravasation; Intravasation; Intravital Imaging; Invasion; Metastasis; Microenvironment; Migration; Mouse Models; Tumour Stroma.

Figure 1.. Tumour metastasis is a vast and interconnected array of dynamic and systemic events encompassing both spatial and temporal events.

The process can be broadly divided into the following stages: ( i) invasion/migration at/near the primary tumour, ( ii) intravasation into the local blood and lymphatic vessels, ( iii) survival and transit of cancer cells in the circulation/lymphatics, ( iv) arrest and extravasation at secondary sites, and ( v) overt colonisation of secondary sites.

Figure 2.. Advances in technologies and tools have allowed us visualise and study some of the stages of metastasis to uncover many of the different mechanisms at play.

( a) Time-lapse intravital imaging of cancer cells (green) in association with blood vessels (red) and collagen fibres—blue, detected by second harmonic generation (SHG)—over the course of 75 minutes shows slow movement (arrowheads) of some cancer cells toward blood vessels. From Pereira et al. . Reused with permission from the American Association for the Advancement of Science. ( b) Tracking the movement of tumour hypoxia using EF5 and pimonidazole probes. Immunofluorescence of KPC xenograft tumours for EF5 (red) and pimonidazole (green) chemical indicators of tumour hypoxia after either (i) co-injection or (ii) 24-hour delayed administration. Images from Conway et al. , under the terms of the Creative Commons Attribution License (CC BY) ( http://creativecommons.org/licenses/by/4.0/). ( c) Confocal images of a spheroid (1:1 mixture of cancer-associated fibroblasts [CAFs] [red] and A431 carcinoma [green] cells) after 60 hours of invasion. CAFs (red) lead collective strands of A431 cells (green). Image, originally published in Labernadie et al. , used with permission from Macmillan Publishers Ltd. ( d) Multicellular seeding is a frequent mechanism for distant metastasis. Via Cre recombinase technology, mosaic (red/green) tumour organoids are created and transplanted into non-fluorescent host mice. After 6 to 8 weeks, the lungs of these mice are harvested. Metastases arising exclusively from single-cell seeding produce only single-colour metastases (red OR green). In contrast, multicellular seeding produces metastases with both colours (red AND green). Representative micrographs of polyclonal lung metastases of different sizes from Cheung et al. . Scale bars = ( a) 50 μm and ( b, c) 100 μm.